Candidate: David C. Calverley, M.D. is a hematologist (Acting Instructor in Medicine, University of Washington) with a research interest in platelets. His goal is to further understanding in the area of platelet adhesion and to identify therapeutic strategies for heart attack and stroke victim, thus combining his scientific training in molecular biology with his clinical training in hematology. Research: Background: Arterial thromboses (heart attacks and strokes) cause major morbidity and mortality. Platelet adhesion to damaged atherosclerotic subendothelium initiates arterial thrombosis and is mediated through a unique shear-dependent receptor-ligand interaction involving platelet glycoprotein lb and von Willebrand factor. Questions: This application asks 'What are the signaling events that link GPIb receptor occupancy to early (within seconds) GPIIb-IIIa conformational change facilitating platelet activation and aggregation?" and "What is the shear-dependent molecular mechanism of the GPIb/vWF interaction?" Methods: The yeast two-hybrid system, immunoprecipitation and confocal microscopy will be used to define protein-protein interactions associated with intracellular signaling directly connecting the GPIb and GPIIb-IIIa cytoplasmic domains through cytosol and membrane skeletal proteins known to interact with these domains. Second, antibodies to gain-of-function GPIb and vWF mutants in a familiar arterial shear flow model will be employed to determine if the receptor and/or ligand alters its conformation reversibly in response to shear. Environment: This project is part of an on-going effort in Dr. Gerald Roth's laboratory at the Seattle VA Medical Center and University of Washington to study the molecular mechanisms of platelet adhesion and activation. Dr. Roth, who combines a broad perspective in hematology with an expertise in platelet molecular biology, will continue to provide scientific and career guidance.